Project 3 - Pathogenesis of CAA-induced Neurovascular dysfunction. Cerebral amyloid angiopathy (CAA) is a common cause of cerebral hemorrhage in the elderly and is likely to contribute to arteriolar dysfunction and ischemic brain injury. The mechanisms underlying CAA formation and the extent to which CAA contributes to neurovascular dysfunction, dementia, and stroke are not clear. The major constituent of CAA in most individuals is the amyloid-p (A[3)peptide, which also forms amyloid plaques in the brain parenchyma in Alzheimer's disease (AD). CAA is present in most cases of AD and also occurs independently. Ap produced by neurons may also be linked to neurovascular dysfunction and CAA. We have found that in amyloid precursor protein (APP) transgenic mouse models that develop CAA, apoE is required for CAA formation and APPsw/apoE4 mice develop almost exclusively CAA with almost no parenchymal deposits. It has also been shown that anti-Ap antibodies can decrease Ap deposition and improve both neuronal structural abnormalities as well as cognitive deficits in APP transgenic mice. Several positive effects of anti-Ap antibodies on cognition in APP transgenic mice appear to be due their ability to neutralize the toxicity of soluble Ap and are independent of plaque removal. Thus, understanding the effects of soluble Ap and CAA and different forms of Ap on vascular dysfunction may provide new insights into the effects of CAA and new treatment strategies for ischemic brain injury and dementia linked to Ap and CAA. The overall hypothesis of this proposal is that soluble Ap and CAA lead to ongoing arteriolar damage that contributes to neurovascular dysfunction and ischemic injury. In addition, we hypothesize that blocking effects of soluble forms of Ap can inhibit Ap induced neurovascular dysfunction and ischemic injury. In Aim 1, we will utilize in vivo imaging (video and multiphoton microscopy) in APPsw/apoE4, apoE4, and control mice to examine arteriolar vasoreactivity and to determine effects of different forms of Ap and CAA on vessel dysfunction. In Aim 2, we will utilize a well characterized isolated arteriolar microvessel preparation to determine whether vasoreactivity abnormalities linked with Ap and CAA require an intact neurovascular unit and Ap production, or are present specifically in microvessels. In Aim 3, we will determine whether and how Ap and CAA contribute to cerebral blood flow (CBF) abnormalities and ischemia by assessing quantitative CBF and damage in an ischemia model in the presence and absence of agents that target different forms of Ap. RELEVANCE TO PUBLIC HEALTH: AD and stroke are the two most common causes of dementia. Understanding how CAA leads to changes in brain blood vessel function may provide important insights and potentially lead to new treatments for stroke and dementia.